This invention relates to polyvinyl alcohol gels, in particular hydrogels, which are suitable for use in the organism, and formed at the site of application (in situ) out of a viscous liquid via partial crystallization and network formation.
Polyvinyl alcohol (PVA), which can be obtained via the hydrolysis of polyvinyl acetate, for example, is almost completely biodegradable, and readily water-soluble at elevated temperature. PVA-based hydrogels can be fabricated with the consistency of biological tissue and cartilage, and exhibit outstanding stability and biocompatibility in the living organism, which stems from the high water content of these gels on the one hand, and lies in the macromolecule itself on the other, which the organism perceives similarly to water due to the numerous hydroxyl groups. For this reason, PVA gels (PVAG) are all but predestined for applications in the living organism, in particular PVAG, which can be manufactured without cross-linking, radiation curing, and the assistance of problematical chemicals.
In the previous methods for manufacturing such PVAG, a solution of PVA is fabricated in a first step at elevated temperatures, e.g., 120° C., which can be cooled to room temperature and poured into a mold. Various methods are subsequently used for gel formation, wherein the PVA solution is frozen at least once, and then thawed again (freeze/thaw). Typically, the solvent is water, the PVA solutions have a concentration Cp of PVA ranging from 5 to 15%, and are cooled at rates of about 0.1° C./min to temperatures of roughly −15 to −30° C., left standing at this temperature for about 1 to 24 hours, and then thawed again at about 0.1 ° C./min. After such a cycle, the PVAG are opaque and very soft. They can already be damaged on contact, the strength sm of a PVAG with Cp=15% measures around 0.04 MPa, and the modulus of elasticity E measures around 0.01 MPa. The mechanical properties are continuously improved by repeating the freeze/thaw treatment, wherein the strength sm measures around 1 MPa, and the modulus of elasticity measures around 0.1 MPa after 10 cycles. Additional cycles further improve the mechanical properties to only a slight extent. These PVAG are copiously described in prior art, e.g., by F. Yokoyama et al in Colloid & Polymer Science (1986), 264, pp. 595-601.
U.S. Pat. No. 4,734,097 describes a modified method, in which only one freeze/thaw cycle is used proceeding from an aqueous PVA solution, e.g., with a Cp=8% in Example 3, and the PVA-water mixture is dehydrated in a frozen state under a vacuum for 10 hours to a concentration Cp of 42%. After thawing, a white opaque gel with a strength sm of 0.5 MPa was obtained, and proposed for use in the human body as artificial tissue. Patents applications were submitted for PVAG manufactured with this method for a plurality of applications, e.g., for artificial organs and membranes in EP 0107055 (artificial organs or membranes for medical use), as dermal gels in EP 0095892 (wound-covering materials), for use as a cooling medium in EP 0070986 (gel for use as cooling medium) as an isolation gel for low temperatures in JP 57190072, as a phantom for NMR diagnosis in GB 2209401 (phantoms for NMR diagnosis), or as a golf ball filling in GB 2182571 (golf ball cores).
U.S. Pat. No. 6,231,605 describes another modified method, in which three freeze/thaw cycles at −20° C. are first executed proceeding from an aqueous PVA solution, e.g., with a Cp=15% in Example 1, after which the obtained gel is placed in water, and swelled in this way. While the gel was transparent in this state, it was so weak that it could not sustain its shape outside of water. The swelled gel subsequently underwent two more freeze/thaw treatments, and then yielded an opaque elastic gel with a modulus of elasticity of roughly 0.4 MPa. Such gels were also proposed as tissue replacement in the human body, e.g., for heart valves, vessels, tendons, cartilage, meniscus, and urethras.
In another modified method in U.S. Pat. No. 4,663,358, the PVA solution is fabricated using mixtures of water and organic solvents, in particular DMSO, and then frozen at −20° C. The obtained gel is subsequently stored in water to largely extract the DMSO, dried in the atmosphere and then dried under a vacuum to extract the remaining DMSO. After swelled in water, the samples yielded PVAG exhibiting a transparency of up to 99% and strengths of up to 5.6 MPa. Such transparent PVAG were proposed for applications in the area of biomedicine and for the food industry.
As mentioned, the cited methods for manufacturing biocompatible PVAG shared in common that the process began with a pourable solution, and at least one freeze/thaw cycle was used. The known methods are obviously not suitable for in situ solvating, during which the PVAG is formed inside the organism at the application site. These applications require that:
1. The PVA-H2O mixture exhibit a sufficiently low viscosity, so that the mixture can be introduced to the application site in the body through a cannula, for example, and
2. Gel formation takes place from the PVA-H2O mixture at body temperature.
Since no methods were initially found that could satisfy these conditions, PVAG were manufactured for biomedical applications outside the body and then implanted. However, the advantages of PVAG formed in situ could not be utilized, e.g., minimally invasive surgical techniques. Methods for fabricating in situ solvating PVAG are based on the chemical cross-linking of injectable PVA solutions. Such methods are described in US 2004 166088 A1, U.S. Pat. No. 6,602,291 and WO 2004 07069296 A1. The disadvantage to these methods is that cross-linking via chemical reactions generates heat, which can damage the surrounding tissue, and that the chemical reaction yields various undesirable byproducts that represent a difficultly calculable risk.
US 2004 0171740 A1 and US 2004 0092653 A1 describe another approach toward in situ solvating PVA solutions. Gel formation here takes place physically, by forming networks via partial crystallization. While this is made possible by elevating the Flory interaction parameters via the addition of salts, the salts must be used in a high concentration (1.5 to 6 molar). As a result, this method also involves the introduction of substances into the organism that are not desirable, and can lead to complications.
This invention describes a solution to the described problems, wherein a solution exhibiting injectable polyvinyl alcohol and water is hardened at body temperature via partial crystallization and network formation into a gel with astounding mechanical properties. No substances other than PVA and water are needed to ensure that this happens. The invention describes the simplest possible case in this regard.